This application for an IP/CP represents a collaborative effort by investigators with expertise in cellular and molecular immunology and in clinical and molecular virology to establish a preclinical and clinical research program. The purpose of the program is to develop and test novel strategies for establishing an effective T cell response to HIV by the adoptive transfer of HIV-specific T cell clones. Methods have been developed in the participating laboratories to isolate, expand, and genetically-modify virus-specific CD4+ and CD8+ T cells in vitro, adoptively transfer immunity by the infusion of such virus-specific T cell clones, and to analyze the effects of therapeutic interventions on viral burden and the generation of viral diversity. Preclinical studies are proposed to promote continued evolution of improved immunotherapeutic strategies, and clinical trials translating these laboratory advances are planned to began in the first year and continue throughout the granting period. The proposal is divided into 3 research projects and two scientific cores. Project 1 will focus on adoptive immunotherapy of HIV infection with autologous HIV-specific CD8+ CTL clones. Clinical studies are designed to determine if improve antiviral effects and sustained immune responses can be achieved by the concurrent administration of T cell clones and IL2. Preclinical studies are evaluating genetic modifications of the CD8+ T cells to provide an antigen-regulated helper-independent phenotype that would bypass the need for exogenous IL2 or CD4+ cells to sustain the CD8+ responses. Project 2 will focus on adoptive immunotherapy of HIV infection with HIV-specific CD4+ T cell clones. Preclinical studies will evaluate the expression of distinct genes in CD4+T cells that can potentially provide protection from infection with HIV. Clinical trials will pursue establishing competent CD4+ T cell response to HIV by transfer of clones genetically-modified to resist HIV and evaluate the immunologic and virologic consequences of such a response. Project 3 will focus on the effects of T cell therapy on virus reservoirs and viral diversity. Specimens will be obtained from patients prior to and after therapy to analyze viral evolutionary dynamics, viral and cell turnover and decay rates, viral migration between compartments, selection pressures, and emerging and waning variants. The three projects are supported by a Virology Core essential for the monitoring of antiviral activity and a retroviral Vector Core capable of producing the vector necessary for the proposed human trials.